G protein coupled receptors (GPCRs) are the major hormone receptors, constituting approximately 3 percent of the human genome. It has been a dogma that, when a hormone1 binds to a GPCR, the liganded receptor activates itself to generate hormone signals (cis-activation). In contrast to this dogmatic cis-activation, the evidence is emerging that a liganded receptor molecule can intermolecularly activate nonliganded receptor molecules (trans-activation). There are only several reports on trans-activation of GPCRs: two on the thrombin receptors and our reports on the LH receptor (LHR). LHR consists of two equal halves, the extracellular N-terminal exo-domain and the membrane associated heptahelical endo-domain. Hormone binds to the exo-domain, whereas the endo-domain generates two distinct hormone signals: one for adenylyl cyclase to produce cAMP (cAMP signal) and the other for phospholipase cbeta to produce diacylglycerol and inositol phosphate (IP signal). Trans-activation is difficult to test, because it has to be differentiated from cis-activation and hormone binding needs to be distinguished from signal generation. LHR meets these requirements and offers a unique model to test trans-activation. We have established a large library of two mutant groups, one deficient in hormone binding and the other deficient in signal generation. Co-expression of a binding deficient mutant and a signal deficient mutant in a cell rescues signal generation. Our preliminary data show that the trans-activation generates either the cAMP signal or IP signal, but not both. Aim 1 will test the hypotheses that trans-activation occurs not only to the mutant receptor pairs but also to the wild type receptor and that the signal selection is specific. Aim 2 will define the mechanistics of the trans-activation and signal selection. These new paradigms will have broad implications on the mechanisms of GPCR signal generation and development of new receptor therapeutics, particularly to control a specific signal without invoking other signals. Receptors generate multiple signals, which is a source of undesirable/toxic side effects of hormone therapeutics.